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United States Patent |
5,602,104
|
Shroot
,   et al.
|
February 11, 1997
|
Polycyclic aromatic derivatives, process for preparing the same and
pharmaceutical and cosmetic compositions containing the same
Abstract
A polycyclic aromatic compound having the formula
##STR1##
and its salts have useful therapeutic and cosmetic action particularly in
psoriasis. In the formula,
X represents --CH.dbd.CH--, O or S,
R.sub.1 represents hydrogen, branched alkyl having 3-15 carbon atoms,
alkoxy having 1-6 carbon atoms or 1-adamantyl, R.sub.2 represents hydroxy,
hydrogen, linear or branched alkyl having 1-15 carbon atoms Or alkoxy
having 1-6 carbon atoms, with the proviso that R.sub.1 and R.sub.2 are not
simultaneously hydrogen, or R.sub.1 and R.sub.2 together with the adjacent
carbon atoms of the naphthalene ring form a 5 or 6 chain ring optionally
substituted by at least one lower alkyl radical, or interrupted by an
oxygen atom,
R.sub.3 represents --CH.sub.2 OH or --COR.sub.4, or --CH.sub.3 when R.sub.1
and R.sub.2 taken together form a 5 or 6 chain ring,
R.sub.4 represents --OR.sub.5 or
##STR2##
R.sub.5 represents hydrogen, alkyl having 1-20 carbon atoms,
monohydroxyalkyl, polyhydroxyalkyl, aryl or aralkyl optionally
substituted, or the residue of a sugar or the radical
##STR3##
p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl,
monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted or the
residue of an amino acid or the residue of an amino sugar, or taken
together form a heterocycle.
Inventors:
|
Shroot; Braham (Antibes, FR);
Eustache; Jacques (Grasse, FR);
Watts; Oliver (Cagnes S/Mer, FR);
Bernardon; Jean-Michel (Nice, FR);
Nedoncelle; Philippe (Grasse, FR)
|
Assignee:
|
Centre International de Recherches Dermatologiques Galderma (Cird (Valbonne, FR)
|
Appl. No.:
|
421235 |
Filed:
|
April 13, 1995 |
Foreign Application Priority Data
Current U.S. Class: |
514/25; 514/42; 514/438; 514/444; 514/448; 514/461; 514/471; 514/473; 536/4.1; 536/17.2; 536/18.2; 536/18.5; 536/55.2; 536/55.3; 549/59; 549/71; 549/72; 549/75; 549/77; 549/78; 549/385; 549/472; 549/496; 549/497; 549/499; 549/501 |
Intern'l Class: |
A01N 043/08; C07D 307/02; C07D 333/16 |
Field of Search: |
549/385,71,78,497,499,501,72,75,77,472
536/4.1,17.2,18.2,18.5,55.2,55.3
514/24,25,42,438,444,461,471,473,448
|
References Cited
U.S. Patent Documents
2153135 | Apr., 1939 | Dickey et al. | 28/1.
|
2532515 | Dec., 1950 | Pines et al. | 260/348.
|
3940502 | Feb., 1976 | Winter et al. | 426/536.
|
4578522 | Mar., 1986 | Eaddy, III | 568/425.
|
Other References
Chemical Abstract vol. 86 No. 6381, Liebscher et al, "Heterocyclic dyes and
intermediates" (1976).
Chebaane, Societe Chimique de France, BCCFAS (1122) pp. 2521-2526, Jan. 12,
1975.
Hawley's Condensed Chemical Dictionary, 11 Ed., 1989, pp. 100.
|
Primary Examiner: Dentz; Bernard
Assistant Examiner: Covington; Raymond
Attorney, Agent or Firm: Cushman Darby & Cushman Intellectual Property Group of Pillsbury Madison &
Sutro, LLP
Parent Case Text
This is a division of application Ser. No. 07/859,046, filed Mar. 27, 1992,
now U.S. Pat. No 5,434,180 which is a division of application Ser. No.
07/580,916, filed Sep. 12, 1990 now U.S. Pat. No. 5,124,475 which is a
continuation-in-part of application Ser. No. 06/887,618, filed Jul. 21,
1986, now abandoned
Claims
What is claimed is:
1. A polycyclic aromatic compound having the formula
##STR20##
wherein X represents O or S,
R.sub.1 represents hydrogen, branched alkyl having 3-15 carbon atoms,
alkoxy having 1-6 carbon atoms or 1-adamantyl,
R.sub.2 represents hydrogen, hydroxy, linear or branched alkyl having 1-15
carbon atoms or alkoxy having 1-6 carbon atoms, with the proviso that
R.sub.1 and R.sub.2 are not simultaneously hydrogen, or R.sub.1 and
R.sub.2 together with the adjacent carbon atoms of the naphthalene ring
form a 5 or 6 carbon ring optionally substituted by at least one lower
alkyl radical, or interrupted by an oxygen atom,
R.sub.3 represents --CH.sub.2 OH or --COR.sub.4 or R.sub.3 represents
--CH.sub.3 when R.sub.1 and R.sub.2 taken together form a 5 or 6 carbon
ring,
R.sub.4 represents
##STR21##
R.sub.5 represents hydrogen, alkyl having 1-20 carbon atoms,
monohydroxyalkyl, polyhydroxyalkyl, aryl or aralkyl optionally
substituted, or the residue of a sugar or the radical
##STR22##
p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl,
monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted as the
residue of an amino acid or the residue of an amino sugar, or taken
together form a heterocycle,
and the salts of said polycyclic aromatic compound of formula I.
2. The compound of claim 1 wherein said alkyl having 1-20 carbon atoms is
methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl or
octadecyl.
3. The compound of claim 1 wherein said monohydroxyalkyl is 2-hydroxyethyl
or 2-hydroxypropyl.
4. The compound of claim 1 wherein said polyhydroxyalkyl is
2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or
the residue of pentaerythritol.
5. The compound of claim 1 wherein said residue of a sugar is a residue
derived from glucose, mannose, erythrose or galactose.
6. The compound of claim 1 wherein said residue of an amino sugar is a
residue derived from glucosamine, galactosamine or mannosamine.
7. The compound of claim 1 wherein r' and r" taken together form a
heterocycle selected from the group consisting of piperidino, piperazino,
morpholino and pyrrolidino.
8. The compound of claim 1 selected from the group consisting of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid,
the methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid,
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid,
the methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid,
the ethylamide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid and
2-hydroxyethyl-5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-f
urane carboxylate.
9. The compound of claim 1 having the formula
##STR23##
wherein X is O or S and
R.sub.5 represents hydrogen or alkyl.
10. A process for preparing a compound having the formula
##STR24##
wherein X represents --CH.dbd.CH--, O or S,
R.sub.1 represents hydrogen, branched alkyl having 3-15 carbon atoms,
alkoxy having 1-6 carbon atoms or 1-adamantyl,
R.sub.2 represents hydrogen, hydroxy, linear or branched alkyl having 1-15
carbon atoms or alkoxy having 1-6 carbon atoms, with the proviso that
R.sub.1 and R.sub.2 are not simultaneously hydrogen, or R.sub.1 and
R.sub.2 together with the adjacent carbon atoms of the naphthalene ring
form a 5 or 6 carbon ring optionally substituted by at least one lower
alkyl radical, or interrupted by an oxygen atom,
R.sub.3 represents --CH.sub.2 OH or --COR.sub.4 or R.sub.3 represents
--CH.sub.3 when R.sub.1 and R.sub.2 taken together form a 5 or 6 carbon
ring,
R.sub.4 represents --OR.sub.5 or
##STR25##
represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl,
polyhydroxyalkyl, aryl or aralkyl optionally substituted, or the residue
of a sugar or the radical
##STR26##
p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl,
monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted as the
residue of an amino acid or the residue of an amino sugar, or taken
together form a heterocycle,
said process comprising
(1) reacting by a coupling reaction of the Wittig or Wittig-Horner type an
aromatic aldehyde having the formula
##STR27##
wherein R.sub.1 and R.sub.2 have the same meanings given above, with a
pentavalent phosphorous derivative having the formula
##STR28##
wherein X and R.sub.5 have the same meanings given above,
A represents (i)--P[X'].sub.3.sup.+ Y.sup.- wherein X' represents aryl and
Y represents an anion of an organic or inorganic acid, or (ii)
##STR29##
wherein Z represents alkoxy, and R and R' represent lower alkyl or taken
together form a dioxane or dioxolane ring, and
(2) effecting a cyclization-aromatization reaction of the product obtained
in step (1), in a chlorinated solvent, in the presence of an acid
catalyst, said reaction optionally being effected under UV radiation.
11. The process of claim 10 wherein A represents
##STR30##
said coupling reaction in step (1) being carried out in the presence of
lithium di-isopropylamide in tetrahydrofuran at a temperature of about
-80.degree. C.
12. The process of claim 10 wherein said cyclization-aromatization reaction
of step (2) is carried out in dichloromethane or chloroform in the
presence of sulfuric acid, paratoluene sulfonic acid or trifluoromethane
sulfonate of trimethylsilyl.
13. A process for preparing a compound having the formula
##STR31##
wherein X represents --CH.dbd.CH--, O or S,
R.sub.1 represents hydrogen, branched alkyl having 3-15 carbon atoms,
alkoxy having 1-6 carbon atoms or 1-adamantyl,
R.sub.2 represents hydrogen, hydroxy, linear or branched alkyl having 1-15
carbon atoms or alkoxy having 1-6 carbon atoms, with the proviso that
R.sub.1 and R.sub.2 are not simultaneously hydrogen, or R.sub.1 and
R.sub.2 together with the adjacent carbon atoms of the naphthalene ring
form a 5 or 6 carbon ring optionally substituted by at least one lower
alkyl radical, or interrupted by an oxygen atom,
R.sub.3 represented --CH.sub.2 OH or --COR.sub.4 or R.sub.3 represents
--CH.sub.3 when R.sub.1 and R.sub.2 taken together form a 5 or 6 carbon
ring,
R.sub.4 represents --OR.sub.5 or
##STR32##
R.sub.5 represents hydrogen, alkyl having 1-20 carbon atoms,
monohydroxyalkyl, polyhydroxyalkyl, aryl or aralkyl optionally
substituted, or the residue of a sugar or the radical
##STR33##
p is 1, 2 or 3, r' and r" present hydrogen, lower alkyl, monohydroxyalkyl,
polyhydroxyalkyl, aryl optionally substituted as the residue of an amino
acid or the residue of an amino sugar, or taken together form a
heterocycle,
said process comprising
(1) reacting by a reaction of the Wittig or Wittig-Horner type an aromatic
aldehyde of the formula
##STR34##
with a pentavalent phosphorus derivative of the formula
##STR35##
wherein R.sub.1 and R.sub.2 have the meanings given above,
A represents (i) --P[X'].sub.3.sup.+ Y- wherein X' represents aryl and Y
represents an anion of an organic or inorganic acid, or (ii)
##STR36##
wherein Z represents alkoxy, and R and R' represent lower alkyl or taken
together form a dioxane or dioxolane ring,
(2) reacting the intermediate compound resulting from step (1), said
intermediate compound having the formula
##STR37##
with a halogen-ester of the formula
##STR38##
wherein X and R.sub.5 have the meanings given above and
X.sub.1 represents Cl and Br, and
(3) effecting a cyclization-aromatization reaction of the product obtained
in step (2).
14. A pharmaceutical composition comprising in a pharmaceutically
acceptable vehicle at least one polycyclic aromatic compound having the
formula
##STR39##
wherein X represents --CH.dbd.CH--, O or S,
R.sub.1 represents hydrogen, branched alkyl having 3-15 carbon atoms,
alkoxy having 1-6 carbon atoms or 1-adamantyl,
R.sub.2 represents hydrogen, hydroxy, linear or branched alkyl having 1-15
carbon atoms or alkoxy having 1-6 carbon atoms, with the proviso that
R.sub.1 and R.sub.2 are not simultaneously hydrogen, or R.sub.1 and
R.sub.2 together with the adjacent carbon atoms of the naphthalene ring
form a 5 or 6 carbon ring optionally substituted by at least one lower
alkyl radical, or interrupted by an oxygen atom,
R.sub.3 represents --CH.sub.2 OH or --COR.sub.4 or R.sub.3 represents
--CH.sub.3 when R.sub.1 and R.sub.2 taken together form a 5 or 6 carbon
ring,
R.sub.4 represents --OR.sub.5 or
##STR40##
R.sub.5 represents hydrogen, alkyl having 1-20 carbon atoms,
monohydroxyalkyl, polyhydroxyalkyl, aryl or aralkyl optionally
substituted, or the residue of a sugar or the radical
##STR41##
p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl,
monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted as the
residue of an amino acid or the residue of an amino sugar, or taken
together form a heterocycle, and the salts of said polycyclic aromatic
derivative of Formula I.
15. The pharmaceutical composition of claim 14 wherein said polycyclic
aromatic compound is present in an amount ranging from 0.00001 to about 5
percent by weight based on the total weight of said composition.
Description
The present invention relates to new polycyclic aromatic derivatives, to
processes for their preparation and to their use in therapeutic and
cosmetic formulations.
These polycyclic aromatic derivatives are usefully employed in the systemic
and topical treatment of dermatologic ailments linked to a keratinization
disorder (differentiation-proliferation) and dermatologic ailments, or
others, with inflammatory and/or immuno-allergic components. They are also
useful in the treatment of degeneratring maladies of the conjunctive
tissue and they exhibit an antitumoral activity. Besides, these
derivatives can be used in the treatment of atopy, be it cutaneous or
respiratory, and in the treatment of rheumatoid psoriasis.
The compounds of the present invention are also useful in the field of
ophthalmology and principally in the treatment of corneopathy.
The polycyclic aromatic derivatives according to the present invention can
be represented by the following general formula
##STR4##
wherein X represents --CH----CH--, O or S,
R.sub.1 represents hydrogen, branched alkyl having 3-15 carbon atoms,alkoxy
having 1-6 carbon atoms or 1-adamantyl,
R.sub.2 represents hydrogen, hydroxy, linear or branched alkyl having 1-15
carbon atoms or alkoxy having 1-6 carbon atoms, with the proviso that
R.sub.1 and R.sub.2 are not simultaneously hydrogen, or R.sub.1 and
R.sub.2 together with the adjacent carbon atoms of the naphthalenic ring,
form a ring having 5 or 6 chains, optionally substituted by at least one
lower alkyl radical, or interrupted by an oxygen atom,
R.sub.3 represents --CH.sub.2 OH or --COR.sub.4, or even --CH.sub.3 when
R.sub.1 and R.sub.2 taken together form a ring having 5 or 6 chains,
R.sub.4 represents --OR.sub.5 or
##STR5##
R.sub.5 represents hydrogen, alkyl having 1-20 carbon atoms,
monohydroxyalkyl, polyhydroxyalkyl, aryl or aralkyl, optionally
substituted, or the residue of a sugar, or even the radical,
##STR6##
wherein p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl,
monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted or the
residue of amino acid or an amino sugar or when taken together they form a
heterocycle,
and the salts of said polycyclic aromatic derivatives of Formula I.
By alkyl radical having 1-20 carbon atoms is meant, principally, methyl,
ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl, and octadecyl.
By lower alkyl is meant a radical having 1-4 carbon atoms, principally,
methyl, ethyl, isopropyl, butyl and tert.butyl.
By monohydroxyalkyl is meant a radical containing 2-3 carbon atoms such as
2-hydroxyethyl or 2-hydroxypropyl.
By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and from
2-5 hydroxy groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,
2,3,4,5-tetrahydroxy pentyl or the residue of pentaerythritol.
By the residue of a sugar is meant the residue derived, for example, from
glucose, mannose or from erythrose or from galactose.
Representative residues of amino sugars include those derived from
glucosamine, galactosamine or mannosamine.
Representative alkoxy-radicals having from 1-6 carbon atoms include
methoxy, isopropoxy and tert.butoxy.
When the radicals r' and r" taken together form a heterocycle, the
heterocycle is, preferably, a piperidino, piperazino, morpholino or
pyrrolidino radical.
When the compounds according to the present invention are provided in the
form of salts, they can be salts of an alkali or alkaline earth metal or
even of zinc, or they can be salts of an organic amine when they have at
least one free acid function (R.sub.3 =COOH), or they can be salts of a
mineral or organic acid, principally the hydrochloride, hydrobromide or
citrate when they have at least one amine function.
Particularly preferred compounds of Formula I according to the present
invention, are those wherein R.sub.3 =COOR.sub.5 and more particularly
those corresponding to formulae A,B,C and D as follows:
##STR7##
wherein R.sub.5 represents hydrogen or alkyl and
R.sub.2 represents branched lower alkyl;
##STR8##
wherein R.sub.5 represents hydrogen or alkyl;
##STR9##
wherein R.sub.1 represents tert.butyl or 1-adamantyl,
and
R.sub.5 represents hydrogen or alkyl;
##STR10##
wherein X represents O or S, and
R.sub.5 represents hydrogen or alkyl.
Certain compounds similar to those of formula (A) are disclosed in U.S.
Pat. No. 4,578,522 where they are noted as being useful for controlling
blood lipids. This difference in utility is thought to be at least in part
a function of the position of the carboxyl group in the respective
molecules.
In this U.S. patent, the carboxyl group is in the ortho position instead of
the para position of formula A above. The importance of the para position
for retinoid mimicry is noted by SPORN et al in "The Retinoids" Vol 1,
especially chapter 3, page 237 and by STRICKLAND et al in Cancer research
43, 5268-5272 (1983) especially page 5271. Both these documents are
incorporated herein by reference.
Representative compounds of Formula I include principally:
p-(6-tert.butyl-2-naphthyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid and
its ethyl, 2hydroxyethyl and 2,3-dihydroxyprophyl esters,
the diethylamide of p-(6-tert.butyl-2-naphthyl) benzoic acid,
the monoethylamide of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid,
p-(6-methoxy-2-naphthyl) benzoic acid and its methyl ester,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzyl alcohol,
2-(p-methylphenyl)-5,6,7,8-tetrahydro5,5,8,8-tetramethyl anthracene,
the p-hydroxyphenyl amide of
p-(5,6,7,8-tetrahydro-5,8,8-tetramethyl-2-anthracenyl) benzoic acid,
p-[7-(1-adamantyl)-6-methoxy-2-naphthyl]-benzoic acid and its methyl ester,
p-(7-tert.butyl-6-methoxy-2naphthyl) benzoic acid and its methyl ester,
p-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoic acid and its methyl ester,
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furan carboxylic
acid and its methyl ester,
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid and its methyl ester,
the ethylamide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furan
carboxylic acid,
the morpholide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furan
carboxylic acid,
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furan
carboxylate of 2hydroxyethyl,
p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho (2,3-b) pyrannyl] benzoic acid
and its methyl ester,
2-(4-methylphenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyanthracene,
Although various synthesis methods can be envisaged in the production of
the compounds of Formula I, it is preferred to employ, in accordance with
the present invention the method represented by the following reaction
scheme:
##STR11##
R and R.sup.1 represent an alkyl radical or taken together form a dioxane
or dioxolane ring.
According to this method, a coupling reaction of the Wittig or
Wittig-Horner type initially is effected between an aromatic aldehyde (1)
and a pentavalent phosphorus derivative (2).
In the derivative (2) the radical A can represent either a triaryl
phosphonium group of the formula:
--P[X'].sub.3 .sup.30 Y-,
wherein X' is aryl and Y is an anion of an organic or inorganic acid, or a
dialkoxyphosphinyl group of the formula:
##STR12##
wherein Z is alkoxy, preferably, --OC.sub.2 H.sub.5.
When A represents -P[X'].sub.3.sup.+ Y.sup.-, the coupling reaction is
carried out in the presence of an alkali metal alcoholate, such as sodium
methylate, or in the presence of an alkylene oxide optionally substituted
by an alkyl group, in a solvent such as methylene chloride or
dimethylformamide. The reaction temperature ranges between 0.degree. C.
and the boiling temperature of the reaction mixture.
When A represents
##STR13##
the condensation is carried out in the presence of a base and, preferably,
in the presence of an inert organic solvent, for example, by means of
sodium hydride or lithium dialkylamide in benzene, toluene,
dimethylformamide (in the case of sodium hydride), tetrahydrofuran,
dioxane or 1, 2-dimethoxyethane, or also by means of an alcoholate, for
example, by means of sodium methylate in methanol or of potassium
tert.butylate in THF, at a temperature between -80.degree. C. and the
boiling point of the reaction mixture. The condensation can also be
carried out by using a mineral base such as KOH or NaOH, in an organic
solvent such as tetrahydrofuran or under phase transfer conditions.
A ring ether, capable of complexing the metallic cation contained in the
base, can be added to the reaction mixture so as to improve its strength.
The intermediate compound of formula (3) is generally obtained in the form
of a mixture of transisomers (E) and cis isomers (Z) that can be separated
by chromatography although the mixture of isomers can be used as such for
the following step.
The cyclization-aromatization reaction is carried out in a chlorinated
solvent such as dichloromethane or chloroform in the presence of, as a
catalyst, a strong acid such as sulfuric acid or p-toluene sulfonic acid
or a silylic ester of a strong acid such as, for example, the
trifluoromethane sulfonate of trimethylsilyl.
When isomer (Z) of the compound of formula (3) or a mixture of (E)-(Z)
isomers is employed the cyclization-aromatization reaction must be
conducted under UV radiation in order to isomerize the isomer (Z) into its
isomer (E).
In effect, under the reaction conditions, the isomers (Z) do not lead to
the expected compounds of Formula I.
This cyclization-aromatization reaction is preferably carried out at
ambient temperature.
The aromatic aldehydes of formula (1) are either available commercially, or
easily accessible by known synthesis methods.
The preparation of the pentavalent phosphorus derivative of formula (2) can
be carried out in accordance with the following reaction scheme:
##STR14##
In accordance with this method a coupling reaction is initially effected
between an alkyl halogeno ester (4) and an acrolein dialkylacetal (5) in
the presence of a palladium salt and a base such as triethylamine,
di-isopropylamine, sodium bicarbonate or sodim carbonate, the temperature
being preferably between 70.degree. and 150.degree. C. The intermediate
compound (6) is then hydrogenated to the compound of formula (7), then
brominated by n-bromosuccinimide in carbon-tetrachloride to provide the
brominated compound (8). This latter compound is then transformed into the
pentavalent phosphorus compound of formula (2) by, for example, the aid of
an organic phosphite such as triethyl phosphite in accordance with the
conditions of the Arbusov reaction.
When the compounds of Formula I, in accordance with the present invention,
are mono-substituted naphthalenic derivatives, (R.sub.1 or R.sub.2
=C.sub.1 -C.sub.15 alkyl) and more particularly the compounds of Formula
II, it is preferred to employ the process represented by the following
reaction scheme:
##STR15##
P= protective group able to generate the carbonyl function X.sub.1 =Cl or
Br.
In accordance with this process a coupling reaction is effected between a
6-halogeno-2-tert.butyl-dimethylsilyloxy naphthalene derivative (9) and a
protected carbonyl derivative of a p-halogenobenzoic acid (10). In
accordance with this process, the compound (10) is transformed into its
magnesium, lithium or zinc form in accordance with methods known in the
literature and coupled with the halogen derivative of naphthalene (9) by
using, as the reaction catalyst, a transition metal or one of its
complexes.
Representative particular catalysts include those derived from nickel or
palladium and, in particular, compounds of Ni.sub.II (NiCl.sub.2) with
various phosphines, in particular diphenyl phosphinoethane.
The coupling reaction is generally effected at a temperature between -20
and +30.degree. C. in an anhydrous solvent such as for example.
dimethylformamide or tetrahydrofuran.
Various protective groups can be used to generate the carbonyl function of
the p-halogenobenzoic acid. However, in accordance with the present
invention an oxazolinyl group is preferably employed.
The benzonaphthalenic derivative of formula (11) is then treated with
tetramethylammonium fluoride in tetrahydrofuran so as to obtain the
naphthol derivative of formula (12). This latter derivative is then
transformed into the trifluoromethanesulfonate derivative of formula (13)
which, on treatment with an appropriate organocupric derivative, provides,
in accordance with the method described by J.E. McMurray et al
(Tetrahedron Letters 24, p. 2723, 1983), the naphthalene derivative of
formula (14) substituted in the 6 portion by an alkyl radical. On removal
of the protective group using HCl in an aqueous solution, compounds of
Formula II are obtained wherein R.sub.5 =H.
To obtain the compounds of Formula I the process represented by the
following reaction scheme can also be employed:
##STR16##
In accordance with this process a Wittig-Horner reaction is effected
between an aromatic aldehyde (1) and a pentavalent phosphorus derivative
(15) in which A has the same meanings as those given for Scheme A above,
the reaction conditions also being the same. The resulting intermediate
compound (16) is then treated with a heterocyclic halogenoester (17) in
accordance with the Heck reaction so as to provide compound (18) which is
then cyclized.
The coupling reaction between the aromatic aldehyde (1) and the pentavalent
phosphorus derivative (15) is carried out, preferably, by the Wittig
reaction (A=--P[.0.].sub.3.sup.+ Br.sup.-) using preferably as the base,
potassium tert.butylate in THF. This provides the stereospecific
production of compound (16) in its Z form. The use of lithium bases, such
as lithium di-isopropylamide, leads to E+Z mixtures of the intemrediate
(16). The Heck reaction is effected, preferably, between 120.degree. and
220.degree. C. (under nitrogen) and the reaction is generally carried out
in the absence of a solvent. Amines having a high boiling point, for
exajple diazabicycloundecene (DBU) can be used as bases but the best
results are obtained using sodium carbonate as finely divided potassium,
with the catalyst used being palladium (II) acetate in the presence of
triphenylphosphine.
Starting with esters and acids obtained above it is possible to produce, in
accordance with known-procedures compounds of Formula I wherein R.sub.3
has any one of the other meanings given above.
The present invention also relates to the intermediate synthesis compounds
represented by the following formula
##STR17##
wherein R.sub.1 and R.sub.2 have the same meanings given above for Formula
I, and
Y represents .dbd.O or
##STR18##
wherein K represents hydrogen or
##STR19##
wherein X and R.sub.5 have the same meanings as those given for Formula I,
and
R and R' represent alkyl or, taken together, form a dioxane or dioxolane
ring.
The present invention further relates to a medicine comprising the
compounds of Formula I as defined above.
These compounds exhibit excellent activity in the inhibition test of
ornithine decarboxylase in nude rats after induction, by "tape stripping".
This test is recognized as a measure of the activity of retinoids of
cellular proliferation phenomena.
These compounds are particularly appropriate for treating dermatologic
ailments linked to a keratinization disorder
(differentiation-proliferation) as well as dermatologic diseases, or
others, having an inflammatory and/or immunoallergic component
principally:
acnes vulgaris, comedons or-polymorphs, solar senile acne and medicinal or
professional ache,
extensive and/or severe forms of psoriasis, and other keratinization
disorders, and principally ichtysoses and ichtysosis-like conditions,
Darier malady,
palmo-plantar keratodermies,
leucoplasies and leucoplasi-like states, lichen plan
all malignant or benign dermatologic proliferations, severe or extensive.
They are also active in the treatment of tumors, of rheumatoid psoriasis,
cutaneous or respiratory atrophies as well as in certain ophthalomogic
problems relating to corneopathies.
The present invention also relates to a medicinal composition containing at
least one compound of Formula I, such as defined above, or one of its
salts, at a concentration, preferably between 0.00001 and 5 percent by
weight relative to the total weight of the composition.
The present invention thus relates to a new medicinal composition intended
principally for the treatment of the above mentioned disorders, comprising
in a pharmaceutically acceptable support, at least one compound of Formula
I and/or one of its salts.
The compounds in accordance with the present invention exhibit, relative to
known retinoids, better stability to light and oxygen, this being
essentially due to the fact that they have no easily Isomerizable or
oxidizable double bonds.
The compounds according to the present invention are generally administered
at a daily dosage of about 0.01 .mu.g/kg to 0.1 mg/kg of body weight.
As the vehicle or carrier for these compositions, any conventional vehicle
can be employed, the active compound being found either in the dissolved
state, or in the dispersed state in said vehicle.
The administration of the compounds of the present invention can be
effected enterally, parenterally, topically or ocularly. When administered
enterally, the medicines can be provided in the form of tablets, gelules,
lozenges, syrups, suspensions, solutions, powders, granules or emulsions.
When administered parenterally, the medicinal compositions can be provided
in the form of solutions or suspensions for perfusion or injection.
When administered topically, the pharmaceutical compositions, based on the
compounds according to the present invention, can be provided in the form
of ointments, tinctures, creams, salves, powders, pads, impregnated
tampons, solutions, lotions, gels, sprays or suspensions.
These compositions for topical administration can be provided either under
anhydrous form or in aqueous form according to clinical indications.
When administered ocularly, the composition is provided principally in
the-form of an eyewash.
The compounds of Formula I, according to the present invention, are also
useful in the cosmetic field, in particular, in body and hair hygiene
compositions and principally for the treatment of skin having a tendency
to age, to improve the growth of hair, to combat hair loss, to combat
against an oily appearance of the skin or hair, in the protection against
the harmful effects of the sun or in the treatment of physiologically dry
skin.
The present invention thus relates to a cosmetic composition containing, in
a cosmetically acceptable vehicle, at least one compound of Formula I or
one of its salts, this composition being provided principally in the form
of a lotion, gel, soap or shampoo.
The concentration of the compound of Formula I in these cosmetic
compositions is between 0.00001 and 2 percent by weight and, preferably,
between 0.00001 and 1 weight percent based on the total weight of the
composition.
The medicinal and cosmetic compositions according to the invention can
contain inert or even pharmacodynamic or cosmetically active additives and
principally: hydrating agents such as thiamorpholinone and its derivatives
or urea; antiseborrheic or anti-ache agents, such as
S-carboxymethylcysteine, S-benzyl-cysteamine, their salts and their.
derivatives, tioxolone or benzoylperoxide; antibiotics such as
erythromycin and its esters, neomycin or tetracyclines; agents promoting
the growth of hair such as "Minoxidil"
(2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its
derivatives,-Diazoxide (7-chloro-3-methyl-1,2,4 benzothiadiazine
1,1-dioxide) and Phenytoin (5,5-diphenylimidazolidine-2,4 dione);
steroidal and non-steroidal anti-inflammatory agents; carotenoids and,
principally, .beta.-carotene; anti-psoristic agents such as anthralin and
its derivatives and 5,8,11,14-eicosatetraynoic and 5,8,11-eicosatriynoic
acids.
The compositions according to the present invention can also contain flavor
improving agents, preservatives, stabilizers, humidity regulating agents,
pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A
and UV-B filters, anti-oxidants such as .alpha.-tocopherol,
butylhydroxyanisole or butylhydroxytoluene.
The following non-limiting examples illustrate the preparation of the
active compounds of Formula I in accordance with the invention as well as
compositions containing these compounds.
EXAMPLE I
Preparation of p-(6-tert.butyl-2- naphthyl) benzoic acid
(a) 6-bromo-2-tert.butyl dimethylsilyloxy naphthene
The following are dissolved in 50 ml of dimethylformamide: 10 g (45 mmoles
of 6-bromo-2naphthol, 5.65 g(55 mmoles) of triethylamine and 0.12 g (1
mmole) of 4-dimethylamino pyridine.
7.55 g (50 mmoles) of tert.butyl dimethylsilyl-chloride are slowly added
and the resulting solution is stirred for three hours at ambient
temperature. The resulting mixture is poured over 200 ml of water, then
acidified with concentrated HCl until a pH of about 1. The solution is
extracted with ether (4.times.100 ml). The etherified solution is then
washed with water, dried over anhydrous sodium sulfate and the solvent
evaporated.
There is thus obtained a pale yellow oil which is purified, by elution with
heptane, on a short silica column. After concentration of the solvent, a
colorless oil which crystallizes is obtained. After drying, 13.2 g (87%
yield) of the expected product is obtained. Melting point:
60.degree.-62.degree. C.
(b) 6-[p-(4,4-dimethyl-2-oxazolinyl)-phenyl]-2-naphthol
100 ml of anhydrous THF are added to a mixture of 15.3 g (60 mmoles) of
p-(4,4-dimethyl-2-oxazolinyl)-bromobenzene, prepared in accordance with
the method of A. Meyers et al, JOC, 29, 2787 (1974), and 1.75 g.(70 m.
at-g) of magnesium. The reaction starts spontaneously and the reaction
mixture is heated at reflux for 3 hours. After cooling, 8.16 g (60 moles)
of anhydrous zinc chloride are added and the resulting mixture is stirred
for 1 hour at ambient temperature. To the resulting white suspension 9.5 g
(28 moles) of the compound obtained in part (a) above and 0.32 g (0.6
mmole) of NiCl.sub.2 /diphenylphosphinoethane are added. The mixture is
stirred for an additional 3 hours. The reaction is stopped by the addition
of a 2M aqueous solution of ammonium chloride. The reaction medium is then
extracted with dichloromethane and the organic phase is washed with water,
then dried over magnesium sulfate. After evaporation of the solvent an
orange oil is obtained which is purified by passage through a short silica
column, using, as the eluant, dichloromethane. After concentration of the
elution solvent, 2-tert.butyldimethylsilyloxy
6[p-(4,4-dimethyl-2-oxazolinyl)-phenyl]naphthalene in the form of a white
solid is obtained. This solid is dissolved in 50 ml of tetrahydrofuran and
treated with 35 ml of a molar solution of tetrabutylammoniumfluoride in
tetrahydrofuran. The reaction mixture is stirred at ambient temperature
for 3 hours, then poured into water and extracted with dichloromethane.
The organic phase, after having been washed with water, is dried over
anhydrous magnesium sulfate and concentrated. An orange oil is obtained
which is purified by elution through a short silica column, using, as the
eluant, a 99/1 mixture of dichloromethane and methanol. The elution
solvents are evaporated, yielding a pale yellow oil which crystallizes.
After recrystallization in hot methanol, 5.5 g of crystals in the form of
pale yellow needles are obtained (64% yield). Melting point:
221.degree.-223.degree. C.
(c) Trifluoromethane sulfonate of
6-[p-(4,4-dimethyl-2-oxazolinyl)-phenyl]2-naphthyl
To a solution of 3.03 g (30 mmoles) of triethylamine, 0.025 g (0.2 mmole)
of 4,4-dimethylaminopyridine and 5 g (15.8 mmoles) of the compound
obtained in part (b) above, in 100 ml of dichloromethane at 0.degree. C.,
4.89 g (17.4 mmoles) of trifluoromethanesulfonic anhydride are added. The
resulting mixture is stirred at ambient temperature for 2 hours and then
poured into water, and acidified to pH 3 by the addition of concentrated
HCl.
The acidified mixture is extracted with dichloromethane. The organic phase,
after having been washed with water, is dried over anhydrous magnesium
sulfate, and then concentrated, thereby providing an oily solid which is
purified by elution through a short silica column using a 3/1 mixture of
hexane/dichloromethane as the eluant.
After having evaporated the elution solvents under reduced pressure an oily
solid is obtained which is recrystallized by hot cyclohexane, yielding 3 g
of a white crystalline solid (42% yield). Melting point:
132.degree.-135.degree. C.
(d) 2-[p-(6-tert.butyl-2-naphthyl)-phenyl-4,4-dimethyl oxazoline
To a mixture of 0.9 g (10 mmoles) of copper cyanide in tetrahydrofuran
cooled to -78.degree. C., there are slowly added with stirring, 8.7 ml of
a 2.3 molar (20 mmoles) hexane solution of tert.butyl lithium.
The mixture is left to stand until its temperature reaches 0.degree. C. It
is then cooled again to -78.degree. C. whereupon 1.5 g (3.3 mmoles) of the
compound obtained in part (c) above are added. The reaction mixture is
again left to stand until its temperature reaches -20.degree. C. at which
point it is stirred for two additional hours. The reaction is stopped by
the addition of a molar aqueous solution of ammonium chloride. The
reaction mixture is then extractd with dichloromethane and the organic
phase is washed with water, dried over magnesium sulfate and concentrated
under reduced pressure.
A pale yellow solid is obtained which is then purified by preparative HPLC
(ZORBAX SIL, diisopropyl ether/iso-octane/triethylamine, 75/25/1),
yielding 0.35 g (30% yield) of a pale yellow solid having a melting point
of 154.degree.-159.degree. C.
(e) p-(6-tert.butyl-2-naphthyl) benzoic acid
0.3 g (0.8 mmole) of the compound obtained in part (d) above is heated to
reflux in 20 ml of a 3M HCl acid solution for 3 hours. A white precipitate
results which is then filtered and redissolved in 20 cc of methonalic NaOH
at 20%. This mixture is heated at reflux for 30 minutes. The white
precipitate that forms is filtered, washed with water and dried at
75.degree. C. under a vacuum for 24 hours.
0.09 g (40% yield) of the expected acid having a melting point of
310.degree.-315.degree. C. is thus obtained.
EXAMPLE II
Preparation of the ethyl ester of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid
(a) Ethyl ester of p-(3,3-dimethoxypropyl) benzoic acid
83.58 g of ethyl p-bromobenzoate are dissolved in 100 ml of dioxane, to
which are successively added 3.83 g of triphenylphosphine, 41.00 g of
acrolein dimethylacetal, 100 g of potassium carbonate and 1.64 g of
palladium (II) acetate.
The resulting mixture is heated to 110.degree. C., while stirring for 16
hours and then filtered over kelite. The kelite filter is washed with
3.times.200 ml of ethyl ether and the wash medium is then dried and
evaporated yielding 90.37 g of a yellow oil that is dissolved in 365 ml of
methanol. 1.46 g of palladium on carbon (5%) are added and hydrogenation
is carried out. When the absorption of the hydrogen is terminated, the
catalyst is removed by filtration on kelite. After evaporation of the
methanol, the residue is chromatgraphed (silica column, 30.times.10 cm,
eluant: 50/50 mixture of dichloromethane and hexane), yielding, after
evaporation of the solvents, 72.77 g (79% yield) of the ethyl ester of
p-(3,3-dimethoxy propyl)-benzoic acid.
(b) Ethyl ester of p-(1-diethoxyphosphoryl-3,3-dimethoxypropyl)-benzoic
acid
70.00 g of the product obtained in part (a) above are dissolved in 1000 ml
of carbon tetrachloride. 1 g of benzoyl peroxide is added and then 49.38 g
of N-bromo succinimide are added by fractions. The resulting mixture is
heated at reflux for 45 minutes, and the succinimide that forms is removed
by filtration on kelite. The solvent is evaporated and the resulting oil
is dried at ambient temperature under a vacuum (1 mm Hg).
The oil thus produced is dissolved in 400 ml of trtethylphosphite, and
heated to 160.degree. C. for 18 hours. The triethylphosphite is evaporated
at 120.degree. C. under vacuum of a water-jet pump. The residues is
deposited on a silica column (30.times.10 cm), then eluted with a 70/30
mixture of ethyl acetate and hexane, yielding 46.64 g (45% yield) of the
ethyl ester of p-(1-diethoxyphosphoryl-3,3-dimethoxypropyl)-benzoic acid.
(c) Ethyl ester of
p-[1-(2,2-dimethoxyethyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
2-naphthyl)-vinyl ]benzoic acid
31.76 g of the phosphonate obtained above in part (b) are dissolved in 75
ml of tetrahydrofuran. This solution is then cooled to -78.degree. C. and
a solution of lithium diisopropyl amide, prepared starting with
diisopropyl amine (12.5 ml) and n-butyllithium (1.6 ml in hexane) in 75 ml
of tetrahydrofuran, are slowly added thereto.
To this resulting red solution there is added a solution of
5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaldehyde (16.08 g) in 50 ml
of tetrahydrofuran. This mixture is stirred initially for 90 minutes at
-78.degree. C. and then for 90 minutes at ambient temperature.
150 ml of water are then added and the mixture is extracted with ether
(3.times.200 ml).
The organic phase is washed with a saturated solution of sodium chloride
and dried over magnesium sulfate. The dried organic phase is filtered. The
solvents are evaporated. The resulting residue is chromatographed on a
silica column (30.times.10 cm) using, as the eluant, a 30/70 mixture of
ethyl ether and hexane.
There are thus obtained successively:
(A) 8.02 g of ethyl
p-[(E)[1-2,2-dimethoxyethyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-n
aphthyl)]-vinyl]-benzoate, having a melting point of 82.degree. C. and
(B) 8.24 g of ethyl
p-[(Z)-[1-(2,2-dimethoxyethyl)-2-(5,6.,7,8-tetrahydro-5,5,8,8-tetramethyl-
2-naphthyl)]-vinyl]benzoate.
The yield of A+B is 50%.
(d) Ethyl ester of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid
(i) Method I
7.02 g of the (E) isomer of the ester obtained in part (c) above are
dissolved in 80 ml of dichloromethane. To this solution there are added 2
ml of the trimethylsilic ester of trifluoromethane sulfonic acid and the
mixture is stirred for 15 minutes at ambient temperature. The
dichloromethane is evaporated and the residue is introduced into the top
of a short silica column (5.times.10 cm) and eluted with a 60:40 mixture
of methylene chloride and heptane. An evaporation of the solvents, 5.65 g
(94% yield) of the ethyl ester of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid
having a melting point of 126.degree. C. are obtained.
(ii) Method II
7.80 g of the (Z) isomer of the ester obtained in part (c) above are
dissolved in 350 ml of dichloromethane. 1 ml of the trimethylsilic ester
of trifluoromethane sulfonic acid is added and the reaction mixture is
placed in a photochemical reactor. The reaction mixture is stirred for 3
hours, at ambient temperature, while it is irradiated (Hanovia average
pressure lamp, without filter). The dichloromethane is evaporated and the
deep green residue is deposited at the top of a silica column (30.times.8
cm) and eluted with a 40:60 mixture of dichloromethane and heptane. After
evaporation of the solvents, 2.67 g (40% yield) of the ethyl ester of
p-(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-anthracenyl)-benzoic acid are
obtained.
EXAMPLE III
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid
7.32 g of the ester obtained in Example II(d) are suspended in 400ml. of
ethanol 38 ml of 5N NaOH are added to this suspension which is then heated
at 60.degree. C. for 60 minutes. The ethanol is evaporated and the residue
is taken up in water (500 ml) and acidified to pH 1 with 6N HCl. It is
then extracted with ether (3.times.500 ml) and the organic phase is dried
over MgSO.sub.4. After filtration and evaporation of the solvents, 30 ml
of the ethyl ester are added to the residue, yielding after stirring and
filtration, 6.25 g (92% yield) of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid
having a melting point of 282.degree. C.
EXAMPLE IV
Methyl ester of p-[7-(1-adamantyl)-6-methoxy-2-naphthyl]-benzoic acid
(a) 3-(1-adamantyl)-4-methoxy benzaldehyde
11.09 g (37 mmoles) of 2-(1-adamantyl)-4bromo anisole dissolved in 85 ml of
THF are slowly added to 1 g of magnesium and an iodine crystal. At the
beginning of the addition, the reaction mixture is heated until the
reaction begins, then the remainder of the solution is added in a manner
to maintain a regular reflux. This reaction mixture is heated at reflux
for 30 minutes after the end of the addition at which point 2.70 g (37
mmoles) of dry DMF are added. The reaction mixture is then stirred for 30
minutes without heating and then-poured into 300 ml of mixture of 2N
aqueous HCl and dichloromethane.
The organic phase is decanted and the aqueous phase is extracted with
dichloromethane. The organic extracts are combined, washed with a
saturated solution of sodium bicarbonate, then with a saturated solution
of sodium chloride, dried over magnesium sulfate, filtered and the
solvents evaporated.
The resulting residue is purified by passage through a silica column
(eluant: 60:40 mixture of dichloromethane and hexane). After evaporation
of the solvents the expected aldehyde, 8.0 g (80% yield) in the form of a
light yellow powder which melts at 180.degree. C. is obtained.
(b) Methyl ester of
p-[1-(2,2-dethoxyethyl)-2-[3-(1-adamantyl)-4-methoxyphenyl]-vinyl]-benzoic
acid
11.42 g (30.51 moles) of the phosphonate obtained in EXAMPLE II(b) are
dissolved in 50 ml of THF. This solution is then cooled to -78.degree. C.
and there is slowly added thereto a solution of lithium di-isopropylamide
which was prepared in a conventional manner starting with 3.4 g (33.58
mmoles) of di-isopropylamine and 2.1 ml (33.56 mmole) of a solution of
N-butyllithium (1.6M in hexane). The red-orange solution thus obtained is
stirred for 30 minutes at -78.degree. C. and a suspension of
3-(1-adamantyl)-4-methoxybenzaldehyde obtained above in part (a) (7.5 g
27.74 moles) in 140 ml of THF is added in fractions thereto. This addition
lasts for about 10 minutes. The reaction mixture is then stirred initially
for 20 minutes at -78.degree. C. and then for 2 hours at 25.degree. C. The
mixture is poured into water and extracted three times with 100ml
ethylether. The organic phase is washed with a saturated solution of
sodium chloride, dried over magnesium sulfate, filtered and the solvents
evaporated. The residue in chromatographed on a silica column, as in
Example II(c), yielding a mixture of two isomers, E and Z, of the methyl
ester of
p-[1-(2,2-dimethoxyethyl)-2-[3-(1-adamantyl)-4methoxyphenyl]-vinyl]benzoic
acid (7.5 g, 53% yield) in the form of a partially crystallized light
yellow oil. This mixture is used as such in the continuation of the
synthesis.
(c) Methyl ester of p-[7-(1-adamantyl)-6-methoxy-2-naphthyl]-benzoic acid
To 6.65 g (13.55 mmole) of the mixture obtained above in part (b) in 400 ml
of dichloromethane, there are added 2 ml of the trimethyl ester of
trifluoromethyl sulfonic acid (TMSOTf). This mixture is irradiated with
ultraviolet (UV) as in Example II(d), for 4 hours. The solvents are
evaporated, then the reaction mixture is purified by passage through a
silica column (eluant: 70:30 mixture of dichloromethane and hexane). The
fractions containing the expected product are concentrated under a vacuum.
The resulting residue is filtered, washed with 300 ml of cold hexane, then
dried under a vacuum at ambient temperature, yielding 4.65 g (80% yield)
of the expected product, in the form of a yellowish white solid which
melts at 245.degree. C.
EXAMPLE V
p-[7-(1-adamantyl)-6-methoxy-2-naphthyl ]-benzoic acid
1.28 g, (3 mmoles) of the ester obtained in Example IV(c) are suspended in
60 ml of methanol. To the suspension are added 6 ml of 5N NaOH and the
mixture is stirred while heating at reflux for 6 hours. 200 ml of methanol
and 200 ml of water are then added and the resulting solution is
concentrated in a manner to remove most of the methanol. 300 ml of
ethylether and 200 ml of 2N HCl are then added and the crude acid
precipitates. The aqueous phase is recovered and 300 ml of THF are added
thereto. The mixture is dried over magnesium sulfate and the solvents
evaporated. The resulting solid is taken up in 300 ml of hexane, filtered
and oven dried at 100.degree. C. under a vacuum, for 16 hours, yielding
1.16 g (98% yield) of the expected acid in the form of a gray-white powder
which melts at 360.degree. C.
EXAMPLE VI
Methyl ester of p-(7-tert.butyl-6-methoxy-2-naphthyl)-benzoic acid
(a) Methyl ester of
p-[1-(2,2-dimethoxyethyl)-2-(3-tert.butyl-4-methoxyphenyl)-vinyl]benzoic
acid
5.49 g (28.56 mmoles) of 3-tert.butyl-4-methoxy-benzoic aldehyde are
dissolved in 100 ml of THF. The solution is cooled to -78.degree. C. and
there is added thereto a solution of lithium di-isopropylamide-(34.55
mmoles) in THF (50 ml), prepared as indicated above. The reaction is
carried out as in EXAMPLE IV(c). After extraction three times with 200 ml
of ether and treatment as in EXAMPLE IV(b), 5.73 g (49% yield) of the
mixture of the expected E and Z esters in the form of a yellow oil are
obtained.
(b)Methyl ester of p-(7-tert.butyl-6-methoxy-2-naphthyl)-benzoic acid
5.67 g (13.74 mmoles) of the mixture of ester obtained in part (a) above
are all dissolved in 400 ml of dichloromethane. 1 ml of TMSOTf is added
and the mixture is irradiated with UV for 2 hours. The solvent is
evaporated and the residue is chromatographed through a silica column
(eluant: 60:40 mixture of CH.sub.2 Cl.sub.2 and hexane), yielding 3.00 g
(63% yield) of the methyl ester of p-(7-tert.butyl-6-methoxy-2-naphthyl)
benzoic acid which melts at 133.degree. C.
EXAMPLE VII
p-(7-tert.butyl-6-methoxy-2-naphthyl) -benzoic acid
The ester obtained in Example VI(b) is dissolved in 60 ml of methanol. 6 ml
of 5N NaOH are added and the mixture is heated at reflux for 1 hour. The
methanol is then evaporated and 300 ml of water are added. This mixture is
extracted five times with 100 ml of ether, dried over MgSO.sub.4, filtered
and evaporated under reduced pressure. The resulting solid is taken up in
100 ml of hexane, filtered and dried, yielding 0.92 g (96% yield) of the
expected acid which melts at 283.degree. C.
EXAMPLE VIII
Methyl ester of p-[7-(1-adamantyl)-6-hydroxy-2-naphthyl ]-benzoic acid
(a) 2-[3-[3-(1-adamantyl)-4-tert.butyl-dimethylsilyloxyphenyl]-allyl ]-1,
3-dioxane
33 g (72.1 mmoles) of [2-(1,3-dioxan-2yl)ethyl ]triphenylphosphonium
bromide are suspended in 100 ml of THF. The suspension is cooled to
0.degree. C. and 8.5 g (75.6 moles) of potassium terbutylate are added in
small amounts. The mixture is left to stand until it,s temperature reaches
20..degree. C. It is then stirred for 1 hour at which point it is cooled
to 0.degree. C. There is then slowly added a solution of
3(1-adamantyl)-4-tert.butyl-dimethylsilyloxybenzaldehyde in 100 ml of TMF.
Once the addition has ended, the mixture is left to stand until its
temperature reaches ambient temperature at which point it is stirred for 2
hours, then poured into water, and extracted with methylene chloride. The
organic phase is decanted, washed with water, dried over MgSO.sub.4 and
the solvents evaporated. The residue is purified by passage through a
silica column (eluant: 50:50 mixture of CH.sub.2 Cl.sub.2 and hexane),
yielding 19.4 g (95% yield) of the expected mixture containing more than
90% of isomer Z, and less than 10% of isomer E.
(b) Methyl ester of
p-[1-[(1,3-dioxan-2-yl)methyl]-2-[3-(1-adamantyl)-4-tert.butyl-dimethylsil
yloxyphenyl]-vinyl]-benzoic acid
There are successively added in a round bottom flask: 19.1 g (40.8 mmoles)
of the dioxane derivative prepared in part (a) above; 8.8 g of methyl
p-bromobenzoate; 183 mg (0.8 mole) of palladium acetate; 428 mg. (1.6
mole) of triphenylphosphine; and 11.3 g (81.6 moles) of finely divided
potassium carbonate. This mixture is heated under nitrogen at 180.degree.
C. for 2 hours. After cooling to ambient temperature, the resulting solid
is treated with a mixture of dichloromethane and water. The organic phase
is decanted, washed with water, dried over MgSO.sub.4, filtered and the
solvents evaporated. The resulting residue is chromatographed on a silica
column (eluant: 80:20 mixture of CH.sub.2 Cl.sub.2 and hexane) to give 9.5
g (39% yield) of the methyl ester of
p-[1-[(1,3-dioxan-2-yl)-methyl]-2-[3-(1-adamantyl)-4-tert.butyl-dimethylsi
lyloxyphenyl]-vinyl]-benzoic acid.
(c) Methyl ester of
p-[7-(1-adamantyl)-6-tert.butyl-dimethylsilyloxy-2-naphthyl]-benzoic acid
9.0 g (14.9 mmoles) of the ester obtained in part (b) above are dissolved
in 400 ml of dichloromethane. 2 ml of TMSOTf are added and the mixture is
stirred for 3 hours 30 minutes under nitrogen and under UV irradiation.
After evaporation of the dischloromethane, the residue is deposited on a
silica column and eluted with a 50:50 mixture of dichloromethane and
hexane. After evaporation of the solvents, the resulting light yellow
solid is stirred in 100 ml of cold hexane. On filtration 4.55 g (58%
yield) of the expected ester in the form of a white powder melting at
185.degree. C. are obtained.
(d) Methyl ester of p-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]-benzoic acid
4.55 g (8.6 mmoles) of the ester obtained in part (c) above are dissolved
in 30 ml of dry THF.
9.5 ml of a molar solution of tetrabutylammonium fluoride in THF are slowly
added. The resulting orange colored solution is stirred for 2.5 hours at
20.degree. C. The THF is evaporated. After adding water the mixture is
extracted three times with 200 ml of ethylether. The organic phase is
washed with a saturated solution of sodium chloride, dried over
MgSO.sub.4, then evaporated. 3.51 g (99% yield) of the expected ester in
the form of a white-to-beige solid which melts at 247.degree. C. are thus
obtained.
EXAMPLE IX
p-[7-(1-adamantyl)6-hydroxy-2-naphthyl]benzoic acid
1.24 g (3 mmoles) of the ester obtained in Example VIII(c) are suspended in
60 ml of methanol. 6 ml of 5N NaOH are added and the mixture is heated at
reflux for 1 hour. The methanol is evaporated and 200 ml of 2N HCl are
added. The mixture is then extracted three times with 400 ml of
ethylether. The organic phase is washed initially with a saturated
solution of sodium bicarbonate and then with NaCl, dried and evaporated.
1.08 g (90% yield) of the expected acid which melts at
295.degree.-300.degree. C. are obtained.
EXAMPLE X
Methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
(a)
2-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-allyl]-1,3-dioxan
e
In a manner analogous to the procedures of Example VIII(a), strating with
25.2 g (55 mmoles) of [2-(1,3-dioxanyl2-yl] triphenylphosphonium bromide
and 10.8 g (50 mmoles of
5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaldehyde, there are
obtained, after chromatography on a silica column (eluant: hexane 95%,
ether 5%), 4 g (66% yield) of
2-[3(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl).allyl]-1,3-dioxane
in the form of a yellow oil.
(b) Methyl ester of
E-5-[1-[(1,3-dioxan-2-yl)methyl]-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl
-2-naphthyl)-vinyl]-2-furane carboxylic acid
9.42 g (30 mmoles) of the substituted dioxane derivative obtained above in
part (a), 6.15 g (30 mmole) of methyl 5-bromo-2-furoate, 135 mg (0.6
mmole) of Pd (OAc).sub.2, 315 mg (1.2 mmole) of P (C.sub.6 H.sub.5).sub.3
and 8.2 g (60 mmole) of finely divided potassium carbonate are heated at
160.degree. C. for 2 hours. 3.07 g (15 mmoles) of methyl bromofuroate, 135
mg of Pd(OAc).sub.2 and 315 mg of P(C.sub.6 H.sub.5).sub.3 are then added
thereto. Beating is continued for an additional 2 hours. The reaction
mixture is then cooled and purified by passage through a silica column
(eluant: 80/20 mixture of dichloromethane and hexane), yielding 7.1 g (53%
yield) of the expected ester which melts at 123.degree.-124.degree. C.
(c) Methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
7 g (16 mmoles) of the ester obtained in part (b) above are dissolved in
200 ml of dichloromethane. This solution is cooled to 0.degree. C. and 1
ml of TMSOTf is added thereto. The mixture is left to stand until the
temperature returns to ambient temperature at which point the mixture is
stirred for 30 minutes. The solvent is evaporated and the residue is
purified by passage through a silica column (eluant: 50/50 mixture of
dichloromethane and hexane). The resulting product can be recrystallized
in hexane to give 5.5 g (96% yield) of the expected ester which melts at
127.degree. C.
EXAMPLE XI
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
5.2 g (14 moles) of the ester obtained in Example X(c) are treated for 4
hours at reflux with 200 ml of 2N methanolic NaOH. The reaction mixture is
then evaporated and the residue is taken up in water, acidified with
concentrated HCl, extracted with ether, washed with water, dried over
MgSO.sub.4, evaporated and recrystallized in a 50:50 mixture of isopropyl
ether and ethyl acetate. There are thus obtained 4.6 g (93% yield) of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid which melts at 229.degree.-230.degree. C.
EXAMPLE XII
Methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid
(a) Methyl ester of
5-[1-[(1,3-dioxan-2-yl)methyl]-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2
-naphthyl) -vinyl]-2-thiophene carboxylic acid
In a round bottom flask there are introduced: 9.42 g (30 mmoles) of the
dioxane derivative obtained in Example X(a), 6.63 g (30 mmoles) of methyl
5-bromo-2-thiophenecarboxylate, 135 mg of Pd(OAc).sub.2, 315 mg (1.2
mmole) of P(C.sub.6 H.sub.5).sub.3 and 8.3 g (60 mmoles) of finely divided
K.sub.2 CO.sub.3. The mixture is heated under nitrogen at 200.degree. C.
for 2 hours. 3.3 g (15 mmoles) of methyl 5-bromothiophene-carboxylate are
then added and the mixture is heated again for 2 hours.
The reaction mixture is imperfectly purified on a silica column (eluant:
80:20 mixture of dichloromethane and hexane) to obtain 5.4 g of a
non-separable mixture under the conditions employed, of the expected
product (60%) and
E-2[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl)-2-naphthyl]-allyl-1,3-dioxa
ne (40%). This mixture is used as such in the continuation of the
synthesis.
(b) Methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid
The mixture obtained in part (a) above, (5.2 g) is dissolved in 100 ml of
dichloromethane. The resulting solution is cooled to 0.degree. C. and 500
.mu.l of TMSOTf are added thereto. The reaction mixture is left to stand
until its temperature reaches 20.degree. C. at which point it is stirred
for 30 minutes. The solvent is evaporated and the resulting residue is
purified by passage through a silica column (eluant: 50-50 mixutre of
CH.sub.2 Cl.sub.2 and hexane). The resulting product can be recrystallized
in cyclohexane to give 2.5 g of the methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid which melts at 147.degree.-148.degree. C.
EXAMPLE XIII
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracenyl)-2-thiophene
carboxylic acid
2.1 g (5.5 moles) of the ester obtained in Example XII(b), are treated at
reflux for 8 hours with 100 ml of 2N methanolic NaOH. The methanol is
evaporated and the residue is taken up in water, acidified with
concentrated HCl, extracted with ether, dried over MgSO.sub.4 and
evaporated. The residue is recrystallized in a 60:40 mixture of isopropyl
ether and ethyl acetate, yielding 5 g (90% yield) of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid which melts at 254.degree.-255.degree. C.
EXAMPLE XIV
Methyl ester of
p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho-[2,3-b]pyranyl]-benzoic acid
(a) Methyl ester of
p-[1-(2,2-dimethoxyethyl)-2-(4,4-dimethyl-6-chromanyl)-vinyl]benzoic acid
In a manner analogous to the procedures of EXAMPLE IV, 6.49 g (17.3 moles)
of phosphonate, prepared in EXAMPLE II(b), dissolved in THF (20ml) are
treated with a solution of lithium diisopropylamide (17.3 moles) in THF
(20 ml). A solution of 6-formylchromane is added and the resulting mixture
is stirred for 2 hours at -78.degree. C. The reaction mixture is then left
to stand until its temperature reaches ambient temperature, at which point
it is poured into water and extracted with ether. The organic phase is
dried over MgSO.sub.4, and the solvents are evaporated. The resulting
residue is chromatographed on a silica Column (eluant: hexane) yielding
950 mg (15% yield) of the E, Z mixture of the methyl esters of p
[[1-(2,2dimethoxyethyl)-2-(4,4-dimethyl-6-chromanyl)]-vinyl]benzoic acid
in the form of a pale yellow oil which is used as such in the continuation
of the synthesis.
(b) Methyl ester of p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho
2,3-b)-pyranyl]benzoic acid
950 g (2.3 mmoles) of the E+Z mixture of esters obtained above in part (a)
are dissolved in 200 ml of dichloromethane. 0.5 ml of TMSOTf is added and
the mixture is irradiated with UV, under nitrogen, while stirring. At the
end of 3 hours, the solvents are evaporated. The resulting residue is
chromatographed on a silica column (4.times.25 cm, eluant-50:50 mixture of
dichloromethane and hexane). On evaporation, 430 mg (54% yield) of the
methyl ester of
p-[3,4(2H)-dihydro-4,4-dimethyl-7naphtho[2,3-b]pyranyl]-benzoic acid which
melts at 153.degree.-154.degree. C. are obtained.
EXAMPLE XV
p-[3,4(2H-dihydro-4,4-dimethyl-7-naphtho 2,3,-b ]pyranyl ]-benzoic acid
370 mg (1.06 mmoles) of the ester obtained in Example XIV(b) are suspended
in 40 ml of methanol. 400 mg of NaOH pellets are added and the mixture is
heated at reflux for 2 hours while stirring. The methanol is evaporated
and 300 ml of water are added. After neutralization with 1N HCl, the
reaction mixture is extracted with ether (3.times.300 ml). The organic
phase is washed with water saturated with NaCl, dried over MgSO.sub.4 and
the solvent are evaporated, yielding 240 mg (68% yield) of
p-[3,4(2H)-dihydro-4,4-dimethyl-7-naphtho[2,3,-b]pyronyl]benzoic acid
which melts at 249.degree.-250.degree. C.
EXAMPLE XVI
Ethylamide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
(a) Chloride of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
1.15 g (3.31 mmoles) of the acid obtained in Example XI are treated with 5
ml of thionyl chloride at 40.degree. C. for 1 hour. The reaction mixture
is evaporated to dryness and the residue is taken up in bezene and
re-evaporated, yielding 1.17 g of a highly crystalline mass that one uses
as such in the continuation of the synthesis.
(b) Ethylamide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
200mg (0.54 mole) of the chloride of the acid obtained above in part (a)
dissolved in 20 ml of dry CH.sub.2 Cl.sub.2 are added to a solution of
ethylamine (184 mg; 4.08 moles) in 1 ml of CH.sub.2 Cl.sub.2. The mixture
is stirred at ambient temperature for 15 minutes. Water is added and the
mixture is acidified to pH 1 with 1N HCl, extracted with CH.sub.2
Cl.sub.2, washed initially with a saturated solution of NaHCO.sub.3, then
with water, dried, the solvents evaporated. 110 mg (54% yield) of the
expected amide which melts at 200.degree. C. are obtained.
EXAMPLE XVII
Morpholide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid
To 200 mg (0.54 mmole) of the chloride of the acid obtained in Example
XVI(a) dissolved in 20 ml of CH.sub.2 Cl.sub.2 are added 237 mg (2.72
mmoles) of morpholine. The mixture is stirred for 15 minutes at which
point water is added. The mixture is then acidified to pH 1 with 1N HCl
and the organic phase is recovered. This organic phase is initially washed
with a saturated solution of NaHCO.sub.3 and then with water, dried over
MgSO.sub.4 and evaporated. The resulting residue is purified by passage
through a silica column (eluant: 95/5 mixture of CH.sub.2 Cl.sub.2 and
acetone). On evaporation of the solvents 193 mg (85% yield) of the
morpholide of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylic acid which melts at 161.degree. C. are obtained.
EXAMPLE XVIII
2-hydroxyethyl
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-furane
carboxylate
340 mg (5.4 mmoles) of ethyleneglycol are dissolved in 1 ml of CH.sub.2
Cl.sub.2. To this solution there are added 86 mg (1.1 mmole) of pyridine
and 200 mg (0.54 mole) of the chloride of the acid obtained in EXAMPLE
XVI(a), dissolved in 20 ml of CH.sub.2 Cl.sub.2. This mixture is stirred
at ambient temperature for 15 minutes at which point water is added. The
resulting mixture is acidified to pH1 with 1N HCl, extracted with
dichloromethane, washed,successively with a saturated solution of sodium
bicarbonate, then with water, dried over MgSO.sub.4 and evaporated. The
resulting residue is passed through a silica column (eluant - 95/5 mixture
of CH.sub.2 Cl.sub.2 and acetone). On evaporation of the solvents 152 mg
(71% yield) of the expected ester which melts at 143.degree. C. are
obtained.
EXAMPLE XIX
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzyl alcohol
300 mg (0.83 mmole) of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid
obtained in EXAMPLE III above are dissolved in THF. 48 mg (1.25 mmoles) of
LiAlH.sub.4 are added and the mixture is stirred initially for 15 minutes
at ambient temperature and then for 10 minutes at reflux. The mixture is
then left to stand until its temperature returns to ambient temperature.
28 .mu.l of a saturated solution of sodium and potassium tartrate are then
added. The mixture is then filtered and the THF is evaporated. The
resulting residue is taken up in hexane and the precipitate that forms is
filtered, yielding 167 mg (57% yield) of the expected alcohol which melts
at 131.degree. C.
EXAMPLE XX
2- (4-methylphenyl)-5,6,7,8 -tetrahydro-5,5,8,8-tetramethylanthracene.
(a) E-2- [-2- (4-methylphenyl) -3-
(5,6,7,8tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) allyl]1,3-dioxane.
1.5 g (5mmoles) of 2-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)
-allyl]-1,3-dioxane, 850mg (5 mmoles) of 4bromotoluene, 25mg (0.1 mmole)
of Pd (OAc).sub.2 55 mg (0.2mmole)of P (C.sub.6 H.sub.5).sub.3 and 1.4 g
(10 mmoles) of potassium carbonate are heated at 180.degree. C. for 2
hours under passage of nitrogen.
The reaction mixture is then cooled and purified by passage over a silica
column eluting with a 50-50 mixture of dichloromethane and hexane. By this
means, 520mg (24%) of the expected product is obtained as a slightly
yellowed oil.
(b) 2-(4-methyl phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylanthracene
480 mg (1.1 mmole) of the derivative above are dissolved in 20 ml of
dichloromethane. On cooling to 0.degree. C., 100 .mu.l of the
trimethylsilyl ester of trifluoromethane sulfonic acid are added while
stirring for 30 minutes at ambient temperature. Next the reaction medium
is poured into water, extracted with ethyl ether, the organic phase
decanted followed by drying on magnesium sulphate before evaporating. The
resulting residue is purified by silica column chromatography using a 95-5
hexane-dichloromethane mixture as eluant. Evaporation of the solvents
yields 310mg (80%) of
2-(4-methylphenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylanthracene which
melts at 91.degree.-2.degree. C.
EXAMPLES OF COMPOSITIONS
A-Orally Administrable Compositions
Example 1
0.29 Tablet
______________________________________
p-(5,6,7,8-tetrahydro-5,5,8,8-
1 .mu.g
tetramethyl-2-anthracenyl)
benzoic acid
Starch 0.114 g
Dicalcium phosphate 0.020 g
Silica 0.020 g
Lactose 0.030 g
Talc 0.0l0 g
Magnesium stearate 0.005 g
______________________________________
In this example the active compound can be replaced by the same amount of
the methyl ester of
5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-2-thiophene
carboxylic acid.
Example 2
0.49 capsule containing a suspension
______________________________________
p-(6-tert.butyl-2-naphthyl)
0.001 g
benzoic acid
Glycerine 0.200 g
Sucrose 0.050 g
Polyethylene glycol 400 0.050 g
Purified water, sufficient
0.400 g
amount for
______________________________________
This suspension is packaged in a capsule made of gelatin, glycerins,
titanium dioxide and water.
In this example the active compound can be replaced by the same amount of
the methyl ester of p-(7-tert.butyl-6-methoxy-2-naphthyl) benzoic acid.
B-Topically Administratable Compositions
Example 1
Ointment
______________________________________
p-(5,6,7,8-tetrahydro-5,5,8,8-
0.0001 g
tetramethyl-2-anthracenyl)
benzoic acid
Stearyl alcohol 3.000 g
Lanolin 5.000 g
Petrolatum 15.000 g
Distilled water, sufficient
100.000 g
amount for
______________________________________
In this example the active compound can be replaced by the same amount of
the ethyl ester of
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2anthracenyl)-benzoic acid.
Example 2
Gel
______________________________________
Ethyl ester of p-(5,6,7,8-
0.005 g
tetrahydro-5,5,8,8-tetramethyl-
2-anthracenyl) benzoic acid
Hydroxypropylcellulose, sold
2.000 g
by Hercules under the trade
designated "KLUCEL HF"
water/ethanol (50:50) sufficient
100.000 g
amount for
______________________________________
In this example the active compound can be replaced by 0.00059 of
p-(7-tert.butyl-6-methoxy-2naphthyl) benzoic acid.
Example 3
Oil-in-water non-ionic cream
______________________________________
2-hydroxyethyl 5-(5,6,7,8-
0.001 g
tetrahydro-5,5,8,8-tetramethyl-
2-anthracenyl)-2-furane
carboxylate
Cetyl alcohol 3.00 g
Stearyl alcohol 3.400 g
Cetyl alcohol oxyethylenated with
0.630 g
20 moles of ehtylene oxide
Stearyl alcohol oxyethylenated
1.470 g
with 20 moles of ethylene
oxide
Glycerol monostearate 2.000 g
Petrolatum oil 15.000 g
Glycerine 10.000 g
Preservative 0.050 g
Distilled water, sufficient
100.000 g
amount for
______________________________________
Example 4
Oil-in-water anionic cream
______________________________________
Ethylamide of 5-(5,6,7,8-
0.002 g
tetrahydro-5,5,8,8-tetra
methyl-2-anthracenyl)-2-
furane carboxylic acid
Sodium dodecyl sulfate 0.800 g
Glycerol 2.000 g
Stearyl alcohol 20.000 g
Triglycerides of capric/caprylic
20.000 g
acid sold by Dynamit Nobel
under the name "MIGLYOL 812"
Preservative 0.050 g
Demineralized water, sufficient
100.000 g
amount for
______________________________________
C - Cosmetic Compositions
Example 1
Anhydrous lotion
______________________________________
Methyl ester of p-[7-(1-adamantyl)-
0.001 g
6-methoxy-2-naphthyl] benzoic
acid
Absolute ethanol 30. g
Polyethylene glycol, sufficient
100 g
amount for
______________________________________
Example 2
Anhydrous gel
______________________________________
p-[7-(1-adamantyl)-6-methoxy-
0.001 g
2-naphthyl] benzoic acid
Monoethylester of diethylene
35 g
glycol
Hydroxypropyl cellulose 1 g
Preservatives, sufficient amount
100 g
Polyethylene glycol, sufficient
amount for
______________________________________
Example 3
Bath Oil
______________________________________
Methyl ester of p-[7-(1-adamantyl)-
0.001 g
6-methoxy-2-naphthyl] benzoic
acid
Ethoxylated fatty alcohol
10.00 g
Octyldodecanol 20.00 g
Isopropyl mysistate 25.00 g
Essential oil 5.00 g
Triglycerides of C.sub.8 -C.sub.10 acid,
100.00 g
sufficient amount for
______________________________________
Example 4
Non-soluble Stick
______________________________________
p-[7-(1-adamantyl)-6-methoxy-
0.001 g
2-naphthyl] benzoic acid
Cocoa butter 12.50 g
Ozokerite wax 18.50 g
Hard paraffin (drop point:
6.25 g
58.degree. C.)
White petrolatum 12.75 g
Isopropyl myristate, sufficient
100.00 g
amount for
______________________________________
Example 5
Shampoo gel
______________________________________
5-(5,6,7,8-tetrahydro-5,5,8,8-
0.002 g
tetramethyl-2-anthracenyl)-2-
furane carboxylate of 2-
hydroxyethyl
Sodium lauryl sulfate 50.00 g
Cocobetaine 20.00 g
Preservatives, sufficient amount
100.00 g
Coloring agent, sufficient amount
Perfume, sufficient amount
Water, sufficient amount for
______________________________________
Example 6
Moderately viscous shampoo
______________________________________
5-(5,6,7,8-tetrahydro-5,5,8,8-
0.002 g
tetramethyl-2-anthracenyl)-2-
furane carboxylate of 2-hydroxy
ethyl
Sodium lauryl ether sulfate
40. g
Diethanolamide of copra fatty
3.00 g
acid
Sodium chloride 2.00 g
Preservatives, sufficient amount
100.00 g
Coloring agent, sufficient amount
Perfume, sufficient amount
Water, sufficient amount for
______________________________________
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